DESCRIPTION: The long term objective of our research is to define the mechanisms responsible for polycythemia vera (PV), a clonal disorder of unknown etiology which involves erythroid, myeloid and megakaryocytic progenitor cells. Recent studies in our laboratory have indicated that PV erythroid progenitor cells, in contrast to normal erythroid progenitor cells, are resistant to the apoptosis associated with erythropoietin (EPO) deprivation. We have also identified a novel signal transduction defect in PV platelets involving thrombopoietin (TPO)-mediated protein tyrosine phosphorylation. These observations have important implications with respect to both the pathogenesis of PV and its clinical manifestations. Based on our observations to date, we now plan to examine TPO-mediated PV platelet signal transduction with respect to platelet c-Mpl expression, the interaction of c-Mpl in PV megakaryocytes as compared to PV platelets. To identify the mechanisms for apoptosis-resistance in PV, using a liquid suspension culture system capable of expanding the population of both normal and PV peripheral blood erythroid progenitor cells, we plan to examine the mechanisms involved in the expression and regulation of Bcl-2 family genes and p53 in the presence and absence of EPO, and using neutrophils as a surrogate model for myeloid cells, to determine whether the apoptosis-resistance associated with growth factor deprivation and its mechanism are global characteristics of PV hematopoiesis.